1.2.4.5- Tetrazines nucleophilic substitution

Substituents bound to the 1,2,4,5-tetrazine ring behave very much as expected. Heterosubstituents can be exchanged by nucleophilic substitution as is shown in Scheme... 

Hetero substitutents exchange readily, though it has been shown that substitution of bromine by amide ion occurs through the Sn (ANRORC) mechanism. Replacement of an amino group with ammonia or hydrazine occurs by both and Sn (ANRORC) mechanisms (84MI5). The only example of this type of nucleophilic substitution in the current literature is the displacement of halogens in tetrazine 288 by alkoxide 289 to yield 290 (85TL4355). 

The similar nucleophilic substitution of chlorine atoms in 53 was applied for incorporation of an S,S-tetrazine phototrigger into alanine-rich a-helical peptides. The tetrazine core constrains the peptide structure, which can be released by UV irradiation exposure (14JOC759). 

A simple route to unsymmetrically substituted 1,2,4,5-tetrazines is the reaction of triethyl orthoformate (or acetate), or DMFDMA, with S-methylisothiocarbonohydrazide salt (9) in the presence of triethylamine and air. The use of iminium chlorides (10) gives similar products. The methylthio group can be readily displaced by nucleophiles to give other substituted tetrazines [94JOC8284],... 

Regioselective nucleophilic, electrophilic, and radical substitution in pyridines, di-, tri-, and tetrazines 88AHC(44)199. 

In comparison with the diazines, the inductive effects of the extra nitrogen(s) leads to an even greater susceptibility to nucleophilic attack and, as a result, all the parent systems and many derivatives react with water, in acidic or basic solution. Similarly, simple electrophilic substitutions do not occur some apparent electrophilic substitutions, such as the bromination of 1,3,5-triazine, probably take place via bromide nucleophilic addition to an N -Br triazinium salt. Attempted direct A-oxidation of simple tetrazines with the usual reagents generally results in ring cleavage, however it can be achieved satisfactorily with methyl(trifluoromethyl)dioxirane. ... 

Bismethylthio-l,2,4,5-tetrazine (25) is an appropriate starting compound for substitution reactions (see Section 6.21.5.3) A-nucleophiles displace one or two sulfur functions. By contrast. 

The synthetic strategy is simple by way of a nucleophilic aromatic substitution—normally using C-, 0-, S-, or A-nucleophiles (303)—a chain with the 27c-unit is anchored to the tetrazine ring (302). The subsequent intramolecular (4 -F 2) cycloaddition (304) (305) follows the normal course of Scheme 53. In most cases alkyne units have been used as the 27i-component, forming bicyclic pyridazines (305) directly. 

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